Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

Abstract

BACKGROUND: Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma and, along with pomalidomide, are being investigated in various other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about their primary mode of therapeutic action in patients with cancer. METHODS: As part of a continuing research effort, we have investigated the effects of these agents on the metastatic capacity of murine colorectal cancer cell lines both in vivo and in vitro. Allied to these, we have studied their effects on the molecular pathways associated with metastasis. RESULTS: Results indicate that thalidomide, lenalidomide and pomalidomide significantly inhibit the metastatic capability of colorectal carcinoma cells. Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence. In addition, an in vivo experimental metastasis model also showed that treatment with the drugs resulted in a significantly lower number of metastatic pulmonary nodules relative to control mice. Allied to these cellular and phenotypic changes were alterations in molecular markers of metastasis and in intracellular signalling competency. CONCLUSIONS: These results provide evidence that in addition to their immunomodulatory effects, thalidomide, lenalidomide and pomalidomide can impair the metastatic capacity of tumours, and that this mechanism may involve alterations to cell signalling functionality.

The immunomodulatory drug lenalidomide restores a vitamin D sensitive phenotype to the vitamin D resistant breast cancer cell line MDA-MB-231 through inhibition of BCL-2: potential for breast cancer therapeutics

“…Its proapoptotic mechanisms include effects on caspases, and inhibition of the antiapoptotic molecule BCL-2 [17]. Lenalidomide also has numerous other anti-cancer properties, such as inhibitory effects on invasion, metastasis, angiogenesis in addition to immunomodulatory effects that enhance NK and T cell function, and inhibit T regulatory cell numbers and function [18][19][20].…”

Pomalidomide suppresses cerulein-induced acute pancreatitis in mice

“…Pharmacokinetic data of pomalidomide in mice are still lacking, but we can expect that the elimination rate of pomalidomide in the mouse would be at least several-fold higher than that in humans, due to the higher metabolic rate in mice. According to published in vivo studies, the dose of pomalidomide used alone to treat mouse models of metastatic colon-rectal cancer and childhood acute lymphoblastic leukemia was 50 mg/kg [35,36]. This is obviously higher than the best therapeutic dose (0.5 mg/kg) for treating acute pancreatitis in the present study.…”

Therapeutic Effect of Lenalidomide in a Novel Xenograft Mouse Model of Human Blastic NK Cell Lymphoma/Blastic Plasmacytoid Dendritic Cell Neoplasm

“…These data suggest, as previously shown in acute myelog- Therapeutic effect of lenalidomide in the human BNKL mouse model So far, lenalidomide has been used to treat hematologic neoplastic diseases such as multiple myeloma, myelodysplastic syndromes (MDS), and lymphoma (15,16,28,29), with some encouraging evidence of possible clinical activity in colorectal carcinoma (30). We therefore decided to test this drug in our model of human BNKL.…”